rs213950

Positions:

chr7-117559479-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000492.4(CFTR):c.1408G>A(p.Val470Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 1,597,726 control chromosomes in the GnomAD database, including 164,304 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.56 ( 26569 hom., cov: 31)

Exomes 𝑓: 0.43 ( 137735 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21

Conservation

PhyloP100: 2.57

Variant links:

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

CFTR links:

CFTR-AS1 (HGNC:):

CFTR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a domain ABC transporter 1 (size 223) in uniprot entity CFTR_HUMAN there are 54 pathogenic changes around while only 9 benign (86%) in NM_000492.4

BP4

Computational evidence support a benign effect (MetaRNN=9.284489E-7).

BP6

Variant 7-117559479-G-A is Benign according to our data. Variant chr7-117559479-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 7130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117559479-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.1408G>A	p.Val470Met	missense_variant	11/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730
CFTR-AS1	NR_149084.1 linkuse as main transcript	n.221+1254C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.1408G>A	p.Val470Met	missense_variant	11/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.557

AC:

84573

AN:

151846

Hom.:

26503

Cov.:

show subpopulations

Gnomad AFR

AF:

0.861

Gnomad AMI

AF:

0.316

Gnomad AMR

AF:

0.518

Gnomad ASJ

AF:

0.277

Gnomad EAS

AF:

0.419

Gnomad SAS

AF:

0.488

Gnomad FIN

AF:

0.562

Gnomad MID

AF:

0.399

Gnomad NFE

AF:

0.415

Gnomad OTH

AF:

0.507

GnomAD3 exomes

AF:

0.475

AC:

119239

AN:

251166

Hom.:

30261

AF XY:

0.464

AC XY:

63030

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.871

Gnomad AMR exome

AF:

0.528

Gnomad ASJ exome

AF:

0.284

Gnomad EAS exome

AF:

0.420

Gnomad SAS exome

AF:

0.480

Gnomad FIN exome

AF:

0.549

Gnomad NFE exome

AF:

0.413

Gnomad OTH exome

AF:

0.452

GnomAD4 exome

AF:

0.427

AC:

616894

AN:

1445762

Hom.:

137735

Cov.:

AF XY:

0.427

AC XY:

307171

AN XY:

720158

show subpopulations

Gnomad4 AFR exome

AF:

0.881

Gnomad4 AMR exome

AF:

0.521

Gnomad4 ASJ exome

AF:

0.283

Gnomad4 EAS exome

AF:

0.406

Gnomad4 SAS exome

AF:

0.475

Gnomad4 FIN exome

AF:

0.547

Gnomad4 NFE exome

AF:

0.403

Gnomad4 OTH exome

AF:

0.438

GnomAD4 genome

AF:

0.557

AC:

84699

AN:

151964

Hom.:

26569

Cov.:

AF XY:

0.561

AC XY:

41636

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.861

Gnomad4 AMR

AF:

0.518

Gnomad4 ASJ

AF:

0.277

Gnomad4 EAS

AF:

0.419

Gnomad4 SAS

AF:

0.488

Gnomad4 FIN

AF:

0.562

Gnomad4 NFE

AF:

0.415

Gnomad4 OTH

AF:

0.510

Alfa

AF:

0.423

Hom.:

33960

Bravo

AF:

0.564

TwinsUK

AF:

0.403

AC:

1493

ALSPAC

AF:

0.391

AC:

1507

ESP6500AA

AF:

0.850

AC:

3747

ESP6500EA

AF:

0.468

AC:

4026

ExAC

AF:

0.483

AC:

58619

Asia WGS

AF:

0.527

AC:

1834

AN:

3478

EpiCase

AF:

0.394

EpiControl

AF:

0.390

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 15, 2008	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 01, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 12, 2020	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Cystic fibrosis

Benign:7

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Apr 03, 2020	- -
Benign, no assertion criteria provided	literature only	OMIM	Nov 01, 1990	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 17, 2015	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	the variant does not result in CFTR-RD neither -
Benign, no assertion criteria provided	clinical testing	Payam Genetics Center, General Welfare Department of North Khorasan Province	Mar 01, 2023	- -

CFTR-related disorder

Benign:4

Benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 19, 2021	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Apr 03, 2020	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Benign

0.72

DEOGEN2

Uncertain

0.53

D;.;.;T;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.68

T;T;T;T;T

MetaRNN

Benign

9.3e-7

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.14

N;.;.;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Benign

0.48

N;.;.;N;.

REVEL

Uncertain

0.46

Sift

Benign

1.0

T;.;.;T;.

Sift4G

Benign

1.0

T;.;.;T;.

Polyphen

0.0

B;.;.;.;.

Vest4

0.069

MPC

0.0040

ClinPred

0.0091

GERP RS

3.0

Varity_R

0.23

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over